Research Interests
Regulation of gene expression by transcription factors, role of receptor tyrosine kinases in cancer malignancies, aberrant gene expression in carcinogenesis, alterations in signal transduction pathways and gene translocations.
Description of Research
The overall goals of the Group are to utilize genomics and proteomics tools and signal transduction resources to accelerate comparative analysis of aberrant gene expression in carcinogenesis and to study alterations in signal transduction pathways during development of cancers.
Cell Survival and Apoptosis
We recently identified the two members of the GADD45 family as key players in apoptosis induction of cancer cells and inhibition of tumor formation. We demonstrated that GADD45α and GADD45γ repression plays an unambiguous and universal role in the ability of tumors to escape programmed cell death. Analysis of in vivo interacting proteins using a mass spectrometry approach identified the cdk11 p58 and a DCND1 (defective in cullin neddylation 1) as partners of the GADD45 family members.
Transcription factors and cancer
A number of transcription factors are overactive in most human cancer cells, making these good targets for the development of anticancer drugs. The epithelium-specific Ets transcription factor, PDEF, plays a role in prostate and breast cancer, although its precise function has not been established. A better understanding of its biology is needed. In prostate cancer PDEF is involved in regulating PSA expression via interaction with the androgen receptor and NKX3.1. Our studies also focus on determining the biological relevance of PDEF in prostate cancer. Current efforts are focused on understanding how the PDEF transcription factor is regulated and, more importantly, degraded.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and MDA-7/IL-24
The third major goal of our Group is to elucidate the molecular mechanisms of cancer apoptosis induction by structurally different Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Our current analysis of NSAIDs treatment of cancer cells demonstrates that NSAIDs mediate apoptosis via induction of the pro-apoptotic cytokine interleukin 24 (IL-24). Our efforts focus on dissecting the molecular mechanisms of apoptosis induction by NSAIDs and on chemically modified versions of NSAIDs as novel entry points that are more specific against cancer and with less adverse reactions. This approach may allow the rational design and treatment with drugs with distinct target specificities that could act synergistically and thus more effectively against cancer.
The Role of tyrosine kinase receptors in cancer development
Our Group also focused on identification of potential therapeutic targets that are upregulated in cancer with particular emphasis on cell surface receptors. We identified several tyrosine kinase receptors whose expression was specifically increased in cancer when compared to control or other subtypes. AXL is most consistently upregulated tyrosine kinase receptor. Our hypothesis is that targeting the AXL tyrosine kinase will inhibit cancer growth and thus lead to a novel therapeutic entry point for cancer.
Recent Publications
Simabuco, F.M., Asara, J.M., Guerrero, M.C., Libermann, T.A., Zerbini, L.F., Ventura, A.M. 2011. Structural Analysis of Human Syncytial Virus P Protein: Identification of Intrinsically Disordered Domains. Braz J Microbiol In Press
Singh, R., Fröbel, J., Cadeddu, R.P., Bruns, I., Schroeder, T., Brünnert, D., Wilk, C.M., Zerbini ,L.F., Haas, R., Czibere, A. 2011. The novel compound OSI-461 induces apoptosis and growth arrest in human acute myeloid leukemia cells. Ann Hematol In press PubMed link
Singh, R., Cadeddu, R.P., Fröbel, J.,Wilk, M., Bruns, I., Zerbini, L.F., Prenzel, T., Hartwig, S., Brünnert, D., Bhasin, M., Schroeder, T., Lehr, S.,Tenen, D.G.,Haas, R.,Czibere, A. 2011. Non-steroidal anti-inflammatory drugs Sulindac sulfide and Diclofenac induce apoptosis and differentiation through an AP-1 and GADD45α dependent pathway in human acute myeloid leukemia cells. Apoptosis 16, 889-901 PubMed link
Zerbini, L.F., de Vasconcellos, J.F., Wang, Y., Paccez, J.D., Gu, X., Zhou, J., Libermann, T.A. 2011. JunD-mediated repression of GADD45a and g regulates escape from cell death in prostate cancer. Cell Cycle 10, 2583-2591 PubMed link
Zerbini, L.F., Tamura, R.E., Correa, R.G., Czibere, A., Cordeiro, J., Bhasin, M., Simabuco, F.M., Wang, Y., Gu, X., Li, L., Sarkar, D., Zhou, J.R., Fisher, P.B., Libermann, T.A. 2011. Combinatorial effect of Non-Steroidal Anti-inflammatory Drugs and NF-kB inhibitors in ovarian cancer therapy. Plos One 6, e24285 PubMed link
Tsuchimochi, K., Otero, M., Dragomir, C., Plumb, D.A., Zerbini, L.F., Libermann, T.A., Komiya, S., Ijiri, K., Goldring, M.B. 2010. GADD45beta enhances Col10a1 transcription via the MTK1/Mkk3/p38 axix and activation of C/EBP beta-TAD4 in terminally differentiating chondrocytes. J Biol Chem 285, 8395-8407 PubMed link
